CN113797160B - Minocycline hydrochloride nano slow-release gel and preparation method and application thereof - Google Patents
Minocycline hydrochloride nano slow-release gel and preparation method and application thereof Download PDFInfo
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- CN113797160B CN113797160B CN202111259966.3A CN202111259966A CN113797160B CN 113797160 B CN113797160 B CN 113797160B CN 202111259966 A CN202111259966 A CN 202111259966A CN 113797160 B CN113797160 B CN 113797160B
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
The minocycline hydrochloride nanometer slow release gel solves the problem of low encapsulation rate of small molecular hydrophilic drugs by introducing minocycline hydrochloride, metal ions and a compound with a plurality of sulfate, sulfonate or phosphate functional groups to chelate to form a novel complex. The minocycline hydrochloride compound emulsion nano-particles prepared are smooth and round, and have high encapsulation efficiency and strong drug carrying capacity. The double-layer delivery system with certain bioadhesion, good periodontal detention and convenient administration is constructed by dispersing the double-layer delivery system in a thermosensitive gel matrix. The invention can obviously reduce the burst release of the medicine while exerting the advantages of gel positioning, is beneficial to prolonging the administration period, creates possibility for the local administration treatment of periodontal pockets of further periodontitis, can penetrate trabecula of alveolar bone and bottom connective tissue, enhances the distribution of the medicine at focus positions, and obviously improves the antibacterial effect of the medicine.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to minocycline hydrochloride nanometer slow-release gel and a preparation method and application thereof.
Background
Periodontitis is a common chronic oral disease that is clinically manifested by inflammatory bleeding of the gums, periodontal pocket formation, loss of adhesion, and destruction of alveolar bone resorption, ultimately leading to loosening and loss of teeth, which is a major cause of loss of teeth in adults. Among the numerous causative factors, bacterial infection is a major factor in inducing and maintaining inflammation, and meanwhile, due to the complex periodontal pocket structure, mechanical scraping is difficult to effectively remove deep microorganisms to cause recurrence of lesions, so that basic mechanical scraping assisted with local antibiotic treatment has become a trend of periodontitis treatment. Heretofore, the marketed periodontal topical sustained release preparations are mainly the following ones: 1. fiber type, trade nameBut is composed ofHas been deactivated by its non-biodegradable nature; 2. a film-type adhesive tape,is an absorbable film product, but has poor variability in size and shape, is easy to fall off after administration, and has poor patient compliance. 3. Microsphere type FDA approved minocycline microsphere +.2001>For the treatment of chronic periodontitis, the use of powdered microspheres is limited because of the difficulty of staying in periodontal disease for a long period of time; 4. gel/ointment type, doxycycline gel->And minocycline hydrochloride ointment->All pass the FDA approval for periodontitis treatment, and the defect is that the slow release effect is poor, and the initial burst release effect is often present. Therefore, research on an ideal local periodontal slow release drug delivery system has important clinical value, and meanwhile, the research is also a current difficult problem and hot spot in the field.
Minocycline hydrochloride is a semisynthetic tetracycline antibiotic and is highly sensitive to various suspicious pathogenic bacteria around the teeth. Minocycline hydrochloride in small dosage can effectively relieve periodontitis reaction, and the medicine is not easy to cause drug resistance of bacteria and does not influence metabolism of normal periodontal tissues. Researches show that minocycline hydrochloride has the effects of inhibiting collagenase activity, preventing tissue destruction and the like besides the effects of resisting bacteria, improving the structure of a tooth Zhou Daijun group and the like, and is a currently accepted first-choice medicament for treating periodontal diseases.
The polymer nanoparticle is a solid colloid particle with the size of 1-1000nm, and has unique advantages compared with other novel preparations in the field of oral disease treatment. For example, due to their small size, nanoparticles can penetrate the trabecular of the alveolar bone, the underlying connective tissue, and even the periodontal pocket area under the gingiva, thereby significantly improving antibacterial effect. Hydrogels are hydrophilic materials with three-dimensional network structures, which play an important role in drug delivery due to their good biocompatibility. The stimulus-responsive hydrogels can achieve controlled drug release and targeted drug delivery by changing the gel structure in a manner that exactly matches physiological needs. Currently, temperature sensitive hydrogels are typical stimulus-responsive hydrogels with good phase transition controllability around physiological temperatures. The temperature sensitive hydrogel presents a transparent liquid state at room temperature, is convenient for realizing injection administration and drug entrapment, and can rapidly gel in a physical crosslinking way when the temperature of the temperature sensitive hydrogel rises and exceeds the critical gel temperature of the temperature sensitive hydrogel after the temperature sensitive hydrogel is injected into a body, thereby realizing in-situ controlled release administration. Dispersing the nano particles in the temperature sensitive hydrogel matrix to construct a composite system is a new drug carrying form which appears in recent years, and can integrate the advantages of the nano preparation and the temperature sensitive hydrogel, so as to obtain a double-layer delivery system which is convenient to administer, stable and long-acting, strong in bioadhesion and good in periodontal detention. In addition, as the nano preparation and the hydrogel jointly control the release of the medicine in the system, the abrupt release of the medicine can be effectively reduced, zero-order release is presented, and the release time of the medicine is prolonged. However, the encapsulation efficiency of small hydrophilic molecules is generally low compared to lipophilic drugs, and it is difficult to achieve effective concentrations at the site of the lesion because the water-soluble drug molecules may be partitioned to the external aqueous phase and subsequently removed before the formulation is cured. The water solubility of the drug can be changed by introducing a compound comprising the drug, metal ions and a plurality of sulfate, phosphate or sulfonate functional groups to chelate to form a novel complex, thereby solving the problem of low encapsulation rate of the small-molecule hydrophilic drug.
Disclosure of Invention
The invention aims at providing a novel periodontitis treatment preparation which meets the local administration requirement of periodontitis, namely minocycline hydrochloride nano slow-release gel.
It is another object of the present invention to provide a method for preparing such a nano sustained release gel.
It is still another object of the present invention to provide a technique that addresses the low encapsulation of small molecule hydrophilic drugs by polymeric nano-formulations.
In order to achieve the above purpose, the following technical scheme is adopted:
the minocycline hydrochloride nanometer slow-release gel is formed by wrapping drug-carrying nanoparticles with temperature-sensitive gel, the nanoparticles have good penetrability in vivo, the distribution of drugs at focus positions can be enhanced, the temperature-sensitive gel has the functions of positioning and slow release, and the two delivery systems are combined by the nanometer slow-release gel to form a double-layer delivery system. 1000mL minocycline hydrochloride nanometer slow release gel comprises the following components: 0.3 to 30g minocycline hydrochloride, 0.1 to 20g metal ions, 0.2 to 100g compound containing a plurality of sulfate, sulfonate or phosphate functional groups, 2 to 300g biodegradable polymer material, 0.5 to 50g emulsifier and 10 to 300g biodegradable hydrogel material. Wherein the mass ratio of minocycline hydrochloride to metal ions is (1.5-4.5): 1, and the mass ratio of the compound containing a plurality of sulfate, sulfonate or phosphate functional groups to the metal ions is (2-5): 1.
The metal ions are one or a mixture of more of iron ions, copper ions, calcium ions and magnesium ions.
The compound containing a plurality of sulfate, sulfonate or phosphate functional groups is one or a mixture of more of sucrose octasulfate, chitosan sulfate, dextran sulfate, polysaccharide sulfonate, cyclodextrin sulfonate and chitosan phosphate.
The biodegradable polymer material is one or more of polylactic acid (PLA), polyethylene glycol-polylactic acid (PEG-PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid (PLGA), polyethylene glycol-polylactic acid-glycolic acid (PEG-PLGA), polycaprolactone (PCL), polycaprolactone-lactide (PCLA) and polymethyl methacrylate (PMMA).
The emulsifier is one or more of povidone, polyvinyl alcohol, polysorbate 80, sodium cholate, sodium deoxycholate and vitamin E polyethylene glycol succinate.
The biodegradable hydrogel material is one or a mixture of more of PEO-PPO-PEO, PLGA-PEG-PLGA, PCLA-PEG-PCLA, PCL-PEG-PCL, PEO-PPO-PCL and chitosan.
The invention also provides a preparation method of the minocycline hydrochloride nanometer slow-release gel, which comprises the steps of firstly preparing minocycline hydrochloride compound emulsion nanoparticles by an emulsification-solvent volatilization method, if concentration is needed, further concentrating the nanoparticles by dialysis, tangential flow ultrafiltration or freeze-drying according to the requirement, and then dispersing the nanoparticles in biodegradable hydrogel. As shown in fig. 1, the specific steps are as follows:
1) Preparation of minocycline hydrochloride compound emulsion nano-particles: minocycline hydrochloride is dissolved in distilled water I, and metal ions and a compound containing multiple sulfate, sulfonate or phosphate functionalities are dissolved in distilled water II to give two internal aqueous phases I and II. The biodegradable polymer material is dissolved in an organic solvent to prepare a high molecular solution, and the high molecular solution is equally divided into two oil phases, namely an oil phase I and an oil phase II. Respectively dripping two parts of internal aqueous phases I and II into an oil phase I and an oil phase II, preparing two W/O colostrum by probe ultrasonic or shearing, uniformly mixing the two colostrum, then performing probe ultrasonic or shearing to obtain W/O emulsion, dripping the W/O emulsion into an external aqueous phase, performing probe ultrasonic or shearing to the external aqueous phase to obtain W/O/W composite emulsion, removing an organic solvent in the obtained W/O/W composite emulsion, and if concentration is needed, further concentrating the nano particles by dialysis, tangential flow ultrafiltration or freeze-drying according to the need to obtain minocycline hydrochloride composite emulsion nano particles, which are also called minocycline hydrochloride composite emulsion nano preparations;
2) Preparing minocycline hydrochloride nanometer slow-release gel: under the condition of continuous stirring, the biodegradable hydrogel material is dissolved in the prepared minocycline hydrochloride compound emulsion nanoparticle to construct minocycline hydrochloride nanometer slow-release gel. The composition schematic diagram of minocycline hydrochloride nano slow-release gel provided by the invention is shown in figure 2.
The preparation method comprises the following steps:
in the step 1), the organic solvent comprises ethyl acetate, dichloromethane, methanol, ethanol, acetonitrile and cyclohexane, preferably dichloromethane.
In the step 1), when two parts of the internal water phases I and II are respectively dripped into the oil phase I and the oil phase II, the volume ratio of the internal water phases to the oil phase is 1:1-1:5.
In the step 1), the obtained W/O emulsion is dripped into an external water phase for ultrasonic or shearing by a probe, and the volume ratio of the oil phase to the external water phase is 1:2-1:10.
The invention also provides application of the minocycline hydrochloride nano slow-release gel, which is applied to preparation of medicines for treating periodontitis diseases.
The method solves the technical problem that the polymer nano preparation has low encapsulation of the small molecular hydrophilic drug.
The bilayer delivery system of the minocycline hydrochloride nano slow-release gel is also suitable for improving the encapsulation rate of other similar hydrophilic small molecule drugs. Such as tetracycline, doxycycline.
The invention has the beneficial effects that:
(1) The invention solves the problem of low encapsulation rate of small-molecule hydrophilic drugs by introducing minocycline hydrochloride, metal ions and a compound with a plurality of sulfate, sulfonate or phosphate functional groups into a form of chelating to form a novel complex.
(2) The minocycline hydrochloride compound emulsion nanoparticle prepared by adopting the emulsification-solvent volatilization method has the particle size of 20-1000nm, is smooth and round, has high encapsulation efficiency and strong drug carrying capacity. The nanometer preparation has strong penetrating power, and the medicine reaches the focus part in the form of nanometer particle, and can obviously improve the antibacterial effect. Then dispersing the nano preparation in a temperature sensitive gel matrix to construct a double-layer delivery system with certain bioadhesion, good periodontal detention and convenient administration. Because the gel material used in the invention has temperature sensitivity, the drug delivery system can be immediately gelled and kept in situ after being injected into a periodontal pocket, and the drug is released from the gel in the form of nanoparticles and penetrates through trabecular and bottom connective tissues of alveolar bones, so that the distribution of the drug at focus positions is enhanced, and the functions of anti-inflammatory activity and reversing the absorption and destruction of the alveolar bones can be exerted to the greatest extent.
(3) Because the release of minocycline hydrochloride is controlled by the double control of the nano particles and the hydrogel, the double-layer drug delivery system constructed by the invention can obviously reduce the burst release of the drug and prolong the drug delivery period while exerting the positioning advantage of the hydrogel.
(4) The nano preparation material and the hydrogel material of the invention are both biodegradable and absorbable materials with biocompatibility, and the nano preparation material and the hydrogel material do not need to be taken out after being used, and do not cause any irritation to tissues.
(5) In the minocycline hydrochloride nanometer slow release gel, the PDI of minocycline hydrochloride nanometer particles is less than 0.2, the drug loading is 2% -10%, the encapsulation efficiency is more than 90%, the accumulated release amount of minocycline hydrochloride nanometer slow release gel for 24 hours is less than 20%, the final accumulated release amount is more than 85%, the minocycline hydrochloride nanometer slow release gel is nearly completely released, and zero-order release is presented.
Drawings
Fig. 1 is a flow chart of minocycline hydrochloride composite emulsion nanoparticle preparation provided by the invention.
Fig. 2 is a schematic diagram of minocycline hydrochloride nano sustained-release gel composition provided by the invention.
Fig. 3 is a transmission electron microscope image, a particle size and a distribution diagram of minocycline hydrochloride composite emulsion nanoparticles provided by the invention.
Fig. 4 is a release graph of minocycline hydrochloride composite emulsion nanoparticles and minocycline hydrochloride nano sustained-release gel provided by the invention.
FIG. 5 is a graph showing the results of the gel temperature measurements of a series of temperature sensitive gels provided by the present invention, wherein A, B, C and D correspond to the results of the gel temperature measurements of four temperature sensitive gels, PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 80:20), PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 50:50), PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 40:60), respectively.
FIG. 6 is a graph showing the results of gel window measurements of two temperature sensitive gels, PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 80:20), PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 50:50), provided by the present invention.
Fig. 7 is a photograph showing the appearance of the blank nano slow release gel and minocycline hydrochloride nano slow release gel provided by the invention before and after gelation.
Fig. 8 shows the results of in vivo experiments of the present invention: the drug effect result of minocycline hydrochloride nanometer slow-release gel for treating periodontitis, namely the expression condition of TNF-alpha and IL-10 of each group of periodontal parts after a period of administration.
Detailed Description
The following examples are further illustrative of the invention and are not meant to be limiting.
Example 1
The preparation method of minocycline hydrochloride nanometer slow-release gel comprises the following steps:
1) Preparation of minocycline hydrochloride compound emulsion nano-particles: 20mg minocycline hydrochloride was dissolved in 1mL distilled water, 8mg magnesium chloride and 15mg sucrose octasulfate sodium were dissolved in another 1mL distilled water to give two inner aqueous phases. 150mg of PLGA was dissolved in 6mL of methylene chloride and split equally as two oil phases. And respectively dripping two parts of inner water phases into two parts of oil phases, preparing two W/O colostrum by probe ultrasonic, uniformly mixing the two colostrum, performing probe ultrasonic treatment, dripping the obtained emulsion into 12mL of outer water phase which is a povidone solution with 2%, removing dichloromethane in the obtained W/O/W compound emulsion by reduced pressure distillation, and concentrating the emulsion appropriately by a dialysis method to obtain minocycline hydrochloride compound emulsion nano particles. The encapsulation rate of the nanoparticle to minocycline hydrochloride is 92%.
2) Preparing minocycline hydrochloride nanometer slow-release gel: 1g of PEO-PPO-PEO is dissolved in 5mL of concentrated minocycline hydrochloride composite emulsion nano particles under the condition of continuous stirring to construct.
Example 2
The preparation method of minocycline hydrochloride nanometer slow-release gel comprises the following steps:
1) Preparation of minocycline hydrochloride compound emulsion nano-particles: 40mg minocycline hydrochloride was dissolved in 2mL distilled water and 18mg calcium chloride and 38mg dextran sulfate were dissolved in another 2mL distilled water to give two internal aqueous phases. 300mg of PCL was dissolved in 5mL of methylene chloride, and the resultant mixture was equally divided into two oil phases. And respectively dripping two parts of inner water phases into two parts of oil phases, preparing two W/O colostrum by probe ultrasonic, uniformly mixing the two colostrum, performing probe ultrasonic treatment, dripping the obtained emulsion into 25mL of outer water phase, performing probe ultrasonic treatment, wherein the outer water phase is 0.5% sodium cholate solution, and removing dichloromethane in the obtained W/O/W compound emulsion by reduced pressure distillation to obtain minocycline hydrochloride compound emulsion nano particles. The encapsulation rate of the compound emulsion nanoparticle to minocycline hydrochloride is 94%.
2) Preparing minocycline hydrochloride nanometer slow-release gel: 2g of PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 50: 50) were dissolved in the minocycline hydrochloride double emulsion nanoparticles described above under continuous stirring.
Example 3
The preparation method of minocycline hydrochloride nanometer slow-release gel comprises the following steps:
1) Preparation of minocycline hydrochloride compound emulsion nano-particles: 80mg minocycline hydrochloride was dissolved in 4mL distilled water, 35mg calcium chloride and 100mg dextran sulfate were dissolved in another 4mL distilled water to give two internal aqueous phases. 720mg of PLGA was dissolved in 8mL of methylene chloride, and the mixture was equally divided into two oil phases. And respectively dripping two parts of inner water phases into two parts of oil phases, preparing two W/O colostrum by probe ultrasonic, uniformly mixing the colostrum, performing probe ultrasonic treatment, dripping the obtained emulsion into 40mL of outer water phase, performing probe ultrasonic treatment, wherein the outer water phase is 1% sodium cholate solution, removing dichloromethane in the obtained W/O/W compound emulsion by reduced pressure distillation, and concentrating by a freeze-drying and reconstitution method to obtain minocycline hydrochloride compound emulsion nano particles. The encapsulation rate of the compound emulsion nanoparticle to minocycline hydrochloride is 95.58%.
2) Preparing minocycline hydrochloride nanometer slow-release gel: 2g of PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 50:50) were dissolved in 10mL of concentrated minocycline hydrochloride double emulsion nanoparticles under continuous stirring.
Example 4
The preparation method of minocycline hydrochloride nanometer slow-release gel comprises the following steps:
1) Preparation of minocycline hydrochloride compound emulsion nano-particles: 300mg of minocycline hydrochloride was dissolved in 5mL of distilled water and 70mg of ferrous chloride and 370mg of chitosan sulfate were dissolved in another 5mL of distilled water to give two internal aqueous phases. 1.5g PEG-PLA was dissolved in 10mL methylene chloride and split equally as two oil phases. And respectively dripping two parts of inner water phases into two parts of oil phases, preparing two W/O colostrum by shearing, uniformly mixing the colostrum, shearing, dripping the obtained emulsion into 30mL of outer water phase, performing ultrasonic treatment by a probe, removing dichloromethane in the obtained W/O/W compound emulsion by reduced pressure distillation, and concentrating by a tangential flow ultrafiltration method to obtain minocycline hydrochloride compound emulsion nano particles, wherein the outer water phase is 1% of vitamin E polyethylene glycol succinate solution. The encapsulation rate of the compound emulsion nanoparticle to minocycline hydrochloride is 91%.
2) Preparing minocycline hydrochloride nanometer slow-release gel: 3g of PLGA-PEG-PLGA is dissolved in 10mL of concentrated minocycline hydrochloride double emulsion nano particles under the condition of continuous stirring.
Example 5
The preparation method of minocycline hydrochloride nanometer slow-release gel comprises the following steps:
1) Preparation of minocycline hydrochloride compound emulsion nano-particles: 100mg minocycline hydrochloride was taken and dissolved in 4mL distilled water, 50mg magnesium chloride and 200mg mucopolysaccharide polysulfonate functional groups were dissolved in another 4mL distilled water to give two internal aqueous phases. 1.5g PCLA was dissolved in 20mL of methylene chloride and equally divided into two oil phases. And respectively dripping two parts of inner water phases into two parts of oil phases, preparing two W/O colostrum by probe ultrasonic, uniformly mixing the colostrum, performing probe ultrasonic treatment, dripping the obtained emulsion into 70mL of outer water phase, performing probe ultrasonic treatment, wherein the outer water phase is 0.5% polyvinyl alcohol solution, and removing dichloromethane in the obtained W/O/W compound emulsion by reduced pressure distillation to obtain minocycline hydrochloride compound emulsion nano particles. The encapsulation rate of the compound emulsion nanoparticle to minocycline hydrochloride is 93%.
2) Preparing minocycline hydrochloride nanometer slow-release gel: 2.5g of PCLA-PEG-PCLA was dissolved in 10mL of concentrated minocycline hydrochloride double emulsion nanoparticles under continuous stirring.
Test example:
quality evaluation of minocycline hydrochloride PLGA nanoparticles
1. Appearance and morphology of nanoparticles
The minocycline hydrochloride nanoparticles prepared in examples 1-5 were visually observed as translucent homogeneous liquids with a yellowish opalescence in appearance. Taking a proper amount of sample in example 3, diluting with distilled water to a proper concentration, taking a proper amount of sample, placing the sample on a copper mesh, sucking off the peripheral redundant liquid by using filter paper, after the sample is completely dried, carrying out negative dyeing for 1min by using 1% phosphotungstic acid, and after the sample is completely dried, observing the form of nanoparticles under a transmission electron microscope, wherein the result shows that the particle size of the nanoparticles is about 100nm, and the nanoparticles are in a round spherical structure and are uniformly distributed (see figure 3A).
2. Particle size and particle size distribution investigation of nanoparticles
Particle size and particle size distribution are a key indicator of nanoformulations, and particle size distribution is generally expressed in terms of polydispersity (polydispersity index, PDI). The particle size and PDI of the nanoparticle are measured by utilizing a dynamic light scattering principle, and the specific operation is as follows: diluting the sample prepared in the example 3 with distilled water, sucking a proper amount of diluent, putting the diluent into a clean sample cell, and setting operation parameters: the temperature was 25℃and the Count rate was adjusted to a value between 200 and 400, and the measurement was performed. The result showed that the nanoparticle had a particle size of 109.2nm and a PDI value of 0.136 (see FIG. 3B).
Zeta potential measurement
Dropping a proper amount of the sample solution prepared in the embodiment 3 into a cuvette by using a rubber head dropper, adding a proper amount of distilled water for dilution, inserting an electrode, not generating bubbles, putting the cuvette into a sample cell, adjusting the light intensity to be about 2000, measuring at room temperature for 2min, and measuring the Zeta potential value to be-44.0+/-7.98 mV.
4. Drug loading and encapsulation efficiency determination
(1) Determination of drug total: precisely sucking 1mL of the sample prepared in the example 3, placing the sample into a 25mL measuring flask, adding about 4mL of acetonitrile, carrying out ultrasonic oscillation for dissolution, adding distilled water to a fixed volume to a scale, uniformly mixing, centrifuging at 15000rpm by a high-speed centrifuge for 10min, taking a supernatant to be measured, and measuring absorbance at a wavelength of 350nm by an ultraviolet-visible spectrophotometer.
(2) Determination of free drug content: about 1mL of the nanoparticle solution prepared in example 3 is taken and placed in an ultrafiltration centrifuge tube (100000 Da), the centrifugation is carried out at 3000rpm for 10min, filtered liquid in the centrifuge tube is taken, the centrifugation is carried out at 15000rpm for 10min by a high-speed centrifuge, the supernatant is taken and tested, and the absorbance is measured at the wavelength of 350nm by an ultraviolet-visible spectrophotometer.
The encapsulation efficiency is calculated as follows:
EE％＝(W total –W free )/W total ×100％
the calculation formula of the drug loading is as follows:
DL％＝(W tota l–Wf ree )/W nanoparticles ×100％
wherein:
W total is minocycline hydrochloride total amount;
W free the amount of free minocycline hydrochloride that is not entrapped;
W nanoparticles is minocycline hydrochloride nanometer preparation.
The drug loading of minocycline hydrochloride in example 3 was calculated to be 9.59% and the encapsulation efficiency was 95.58%.
5. Drug release behavior investigation
The in vitro release of minocycline hydrochloride was examined by dialysis. The specific operation is as follows: weighing a proper amount of the sample solution prepared in the example 3, placing the sample solution into an activated dialysis bag (MWCO=14000 Da), sealing two ends of the dialysis bag, placing the dialysis bag into a release small bottle, adding a proper amount of release medium (PBS; 0.01M, pH 7.4) to completely soak the dialysis bag, placing the release small bottle into a water bath shaking table with the set rotating speed of 100rpm/min and the temperature of 37+/-0.5 ℃ for constant-temperature shaking. At each preset time point, all release medium was removed and an isothermal equal volume of fresh medium was added. Taking out the release medium, centrifuging at 15000rpm for 10min, taking supernatant to be tested, measuring the accumulated release amount of the drug at each time point by adopting an ultraviolet-visible spectrophotometry at an absorption wavelength of 350nm, taking the release time as an abscissa and the accumulated release percentage of the drug as an ordinate, and drawing an in-vitro release curve. The release result shows that minocycline hydrochloride nano-particles are released to 52.25% in the first 24h, and the abrupt release phenomenon exists. The cumulative drug release profile of minocycline hydrochloride PLGA nanoparticles of example 3 is shown in FIG. 4.
Rheological Property investigation of gel
1. Gel gelation temperature determination
The temperature sensitive gel material is an amphiphilic polymer, and can gel under the proper concentration and temperature conditions. Storage modulus is also called elastic modulus, and refers to the magnitude of energy stored by elastic (reversible) deformation when a material is deformed, and reflects the elastic magnitude of the material; the energy consumption modulus is also called as viscous modulus, and refers to the energy loss caused by viscous deformation (irreversible) when the material is deformed, and reflects the viscosity of the material; when the storage modulus and the loss modulus are comparable, the material is semi-solid, and the temperature at this point is the gelation temperature (Tgel). Tgel is an important parameter of temperature sensitive hydrogels, which is detrimental to the preparation and application of the formulation when Tgel is below room temperature; when Tgel is higher than the temperature of the oral cavity, the injection into the periodontal pocket cannot gel, and the positioning and slow-release effects are not exerted. Tgel of an acceptable oral thermal gel solution must be in the range of 30-35 ℃ in order to be liquid at room temperature and form a gel phase immediately in the periodontal pocket. PLGA-PEG-PLGA, PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 80:20), PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 50:50), and PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 40:60), the gel temperature measurement results of these four temperature-sensitive hydrogel materials correspond to A, B, C and D of FIG. 5, respectively, the gel temperature is 36.4 ℃, 33.7 ℃, 31.5 ℃ and 29.5 ℃ in order. The results show that PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 80:20), PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 50:50) have the gelation temperature suitable for periodontal pocket drug administration, the hydrogels prepared by the two hydrogel materials are in a liquid state at room temperature, the needle penetrating property is good, and gel phases can be formed immediately after the hydrogel materials are injected into periodontal pockets and fixed at focus positions, so that the drugs are continuously and slowly released at focus positions.
2. Inspection of the gel window of the gel
According to the test tube inversion method, PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 80:20) are obtained, and the phase diagrams of the gel prepared by the PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 50:50) are shown in figure 6. The results show that PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 50: 50) have a wider gel window than PLGA-PEG-PLGA and PCLA-PEG-PCLA (m/m 80: 20), and are more suitable for use as a temperature sensitive gel material for periodontal pocket topical administration.
Quality evaluation of minocycline hydrochloride nanometer sustained-release gel
1. Appearance of
The temperature-sensitive gel is in a solution state at low temperature and can flow freely; when the temperature is higher than the critical gelation temperature, gelation occurs, and becomes a non-flowable gel state having high viscosity. See fig. 7.
2. Content determination
Precisely sucking 1mL minocycline hydrochloride nanometer slow-release gel, placing into a 100mL measuring flask, adding 19mL acetonitrile, performing ultrasonic oscillation to dissolve, fixing the volume to the scale with distilled water, uniformly mixing, centrifuging at 15000rpm by a high-speed centrifuge for 10min, and taking the supernatant to be measured. Absorbance was measured at a wavelength of 350nm using an ultraviolet-visible spectrophotometer. The minocycline hydrochloride content in the minocycline hydrochloride nanometer slow release gel is 1.286mg/mL through calculation.
3. Drug release behavior investigation
Taking minocycline hydrochloride nano slow release gel prepared in example 3, placing in a shaking table at 37 ℃ for 10min in advance, and adding a pre-heated release medium (37 ℃) after phase change gelation occurs. The accumulated release condition of the medicine is inspected by adopting a dialysis method, and the release condition and the measurement method are the same as those of minocycline hydrochloride nano-particles. And drawing an in-vitro release curve by taking the release time as an abscissa and the accumulated release percentage of the drug as an ordinate. The drug cumulative release profile of minocycline hydrochloride nano-sustained release gel of example 3 is shown in figure 4. The release result shows that the cumulative release amount of minocycline hydrochloride nanometer slow release gel for 24 hours is lower than 20 percent, the final cumulative release amount is higher than 85 percent, the release is close to complete release, and zero-order release is presented.
4. Pharmacodynamics investigation of minocycline hydrochloride nano slow-release gel
And (3) constructing a periodontitis model: after SD rats were anesthetized, the interdental gap between the first and second molars of the left upper jaw was separated with a dental probe, an orthodontic stainless steel wire with a diameter of 0.2mm was used to ligate the gap between the first and second molars of the left upper jaw of the rats, the ligature wire was held by forceps and was put into the gap between the first and second molars of the inner side of the upper jaw of the rats, after one week around the upper teeth of the gap, the state of the rats was fixed by knotting in the middle of the side of the palate, and the rats were observed after the operation until all the rats were awakened, and fed with a high sugar diet (composition of high sugar periodontitis diet: 28g of nonfat milk powder, 6g of flour, 56g of sucrose, 4g of yeast powder, 1g of liver powder, a small amount of salt and fresh vegetables) was assisted. After Zhou Jieza weeks, periodontal tissue of the ligature teeth was observed, and gingival redness and swelling were observed with naked eyes, bleeding was detected, gingival crevicular fluid was increased, periodontal pockets were formed, and it was confirmed that periodontitis model establishment was completed.
The grouping is as follows:
healthy group: 8 normal rats, without any treatment;
control group: 8 rats with periodontitis model, without any treatment;
MIN-NPs-in-gel group: 8 rats with periodontitis models are treated by minocycline hydrochloride nanometer slow-release gel;
solution group: 8 rats with periodontitis models are treated by minocycline hydrochloride solution;
the in vivo drug effect result shows that the minocycline hydrochloride nanometer sustained-release gel obviously reduces the expression of TNF-alpha and IL-10 in the periodontal tissue of a model rat, and the minocycline hydrochloride solution group is also reduced, but the reduction degree is obviously inferior to that of the nanometer sustained-release gel group, as shown in figure 8. The gel material used by the nanometer slow-release gel has temperature sensitivity, so that the nanometer slow-release gel can be immediately gelled and kept in situ after being injected into periodontal pockets, and the medicine is continuously and slowly released from the gel in the form of nanoparticles to penetrate trabecula of alveolar bone and connective tissues at the bottom layer, thereby enhancing the distribution of the medicine at focus positions and exerting anti-inflammatory activity to the greatest extent.
Comparative example:
20mg of minocycline hydrochloride was dissolved in 2% (W/V) PVA solution as the aqueous phase and 150mg of PLGA was weighed into 10mL of methylene chloride to prepare the organic phase. The organic phase was added dropwise to the aqueous phase, and the colostrum was prepared by shearing with a high-speed shearing machine under ice bath for a suitable time, and the colostrum was diluted in twice the volume of 2% aqueous sodium chloride solution, and the organic solvent was removed by stirring with ice bath. Centrifuging at 18000rpm for 15min, collecting minocycline hydrochloride nanoparticles, washing with 2% sodium chloride aqueous solution for three times, and lyophilizing. The nanoparticle has a particle size of 261.5nm and a PDI of 0.317 as measured by dynamic light scattering. The encapsulation efficiency of the nanoparticles is about 40%. The drug loading rate of the minocycline hydrochloride PLGA nano particles prepared by the invention is 2% -10%, and the encapsulation rate is more than 90%, which indicates that the technology provided by the invention effectively solves the problem of low minocycline hydrochloride encapsulation rate by introducing a compound which is formed by chelating minocycline hydrochloride, metal ions and a plurality of sulfate, sulfonate or phosphate functional groups into a form of novel complex.
Claims (6)
1. The minocycline hydrochloride nano slow release gel is characterized by comprising the following components in 1000mL of minocycline hydrochloride nano slow release gel: 0.3-30 g minocycline hydrochloride, 0.1-20 g metal ions, 0.2-100 g dextran sulfate, 2-300 g PLGA, 0.5-50 g emulsifying agent and 10-300 g biodegradable hydrogel material; the nanometer slow-release gel is formed by wrapping drug-carrying nanoparticles by using temperature-sensitive gel, the penetrability of the nanoparticles in vivo is good, the distribution of the drug at a focus part can be enhanced, the temperature-sensitive gel has the functions of positioning and slow release, and the two delivery systems are combined by the nanometer slow-release gel to form a double-layer delivery system;
the biodegradable hydrogel material is prepared from PLGA-PEG-PLGA and PCLA-PEG-PCLA in a mass ratio of 80:20 or PLGA-PEG-PLGA and PCLA-PEG-PCLA in a mass ratio of 50:50;
the mass ratio of minocycline hydrochloride to metal ions is (1.5-4.5): 1, and the mass ratio of dextran sulfate to metal ions is (2-5): 1;
the preparation method of minocycline hydrochloride nanometer slow-release gel comprises the following steps:
1) Preparation of minocycline hydrochloride compound emulsion nano-particles: minocycline hydrochloride is dissolved in distilled water I, and metal ions and dextran sulfate are dissolved in distilled water II to obtain two internal water phases I and II; dissolving PLGA in an organic solvent to prepare a high molecular solution, and dividing the high molecular solution into two oil phases, namely an oil phase I and an oil phase II; respectively dripping two parts of inner aqueous phases I and II into an oil phase I and an oil phase II, wherein the volume ratio of the inner aqueous phases to the oil phase is 1:1-1:5, preparing two W/O colostrum by probe ultrasonic or shearing, then uniformly mixing the two colostrum to obtain a W/O emulsion, then dripping the W/O emulsion into an outer aqueous phase by probe ultrasonic or shearing, wherein the volume ratio of the oil phase to the outer aqueous phase is 1:2-1:10, the outer aqueous phase contains an emulsifier to obtain W/O/W composite emulsion, removing an organic solvent in the obtained W/O/W composite emulsion, and further concentrating the nano particles by a dialysis, tangential flow ultrafiltration or freeze-drying method to obtain minocycline hydrochloride composite emulsion nano particles;
2) Preparing minocycline hydrochloride nanometer slow-release gel: under the condition of continuous stirring, the biodegradable hydrogel material is dissolved in the prepared minocycline hydrochloride compound emulsion nanoparticle for construction.
2. The minocycline hydrochloride nano slow release gel according to claim 1, wherein the metal ion is a mixture of one or more of iron ion, copper ion, calcium ion and magnesium ion; the emulsifier is one or more of povidone, polyvinyl alcohol, polysorbate 80, sodium cholate, sodium deoxycholate and vitamin E polyethylene glycol succinate.
3. The minocycline hydrochloride nano-sustained release gel according to claim 1, wherein the minocycline hydrochloride nano-sustained release gel has a cumulative release of less than 20% for 24h, a final cumulative release of greater than 85%, a near complete release, and exhibits zero order release.
4. The minocycline hydrochloride nano slow release gel according to claim 1, wherein the particle size of the prepared minocycline hydrochloride double emulsion nano particles is between 20 and 1000 nm; the PDI is less than 0.2, the drug loading is 2% -10%, and the encapsulation efficiency is more than 90%.
5. The minocycline hydrochloride nano slow release gel according to any one of claims 1-4, which is characterized by being applied to preparation of medicines for treating periodontitis diseases.
6. The minocycline hydrochloride nano slow release gel according to any one of claims 1-4, which is used for improving the encapsulation efficiency of hydrophilic small molecule drugs, wherein the hydrophilic small molecule drugs comprise tetracycline and doxycycline.
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